Prof Dr
Hala Gabr
Prof of Clinical Pathology
Faculty of Medicine, Cairo University
Director of BMT Lab
 Lung
diseases remain a devastating cause of
morbidity and mortality worldwide.
 Unlike many other major diseases, a number
of lung diseases, particularly chronic
obstructive pulmonary diseases (COPDs)
including both asthma and emphysema, are
increasing in prevalence and COPD is
expected to become the third leading cause
of disease mortality worldwide by 2020.
Although important advances in symptomatic
treatments have occurred, many lung diseases
including asthma, emphysema, pulmonary
fibrosis, cystic fibrosis, and others have no cure.
 Lung transplantation is an option; however, there
is a critical shortage of donor lungs and
transplantation is complicated by acute and
chronic rejection requiring lifelong
immunosuppression. Further, 5-year mortality
following lung transplantation is ~50%.
 New approaches for lung diseases are thus
desperately needed.

 "It's
a paradigm shift," says Andre Terzic,
M.D., Ph.D., director of Mayo Clinic's Center
for Regenerative Medicine and senior
investigator of the stem cell trial. "We are
moving from traditional medicine, which
addresses the symptoms of disease, to being
legitimately able to cure disease."
A
stem cell is a clonal, self-renewing entity
that is multipotent and thus can generate
several differentiated cell types
 The
concept of stem cells originated at the
end of the 19th century to account for the
ability of certain tissues (blood, skin) to selfrenew despite the fact that they are
composed of short-lived cells.
 This was only a hypothesis
 In
1960, Till & McCulloch, demonstrated that
a certain population of bone marrow cells,
when injected in mouse spleen, formed
colonies of differentiating cells (CFU-S).
 They proved the clonal nature of the
colonies.First concept: Differentiation
 In
the same year, with the help of Lou
Siminovitch, a molecular biologist, they
proved the self renewal potential of these
cells.
 2nd Concept: Self-renewal
 During
the subsequent decades, all research
focused on characterization & trial of
isolation of this stem cell population
 Two major scientific breakthroughs gave a
great push to stem cell research:


Commercial cytokines
Immunophenotyping using flowcytometry
 The
first logical use of BM stem cells was in
hematological disorders.
 BMT for hematological and nonhematological malignancies began and the
technique postulated & proved the third
stem cell characteristic: 3rd Concept:
Homing.
 The
first sucessful BMT was performed back
in 1968 for treatment of SCID.
 The
observations that there are circulating
CD34+ve cells which can be increased by
certain agents, introduced PBSCT as an
alternative to BMT.
 Stem
cell factors were the last cytokines to
be synthesized. For many years there was a
dogma that “Stem cells cannot be grown or
expanded in-vitro” and we had to use
experimental animals.
 The introduction of SCF gave way to proving
the 4th concept: Proliferation
 Observations
after BMT or PBSCT paved the
way for the last & most interesting concept:
5th concept: Plasticity


Observations following gender-mismatched transplants
Observations following multiple myeloma patients &
effect on kidneys
 Definition:
 Transdifferentiation
means the conversion of
stem cells from one committed lineage to
the other.
 Types:
 A. Spontaneous: one of the normal
mechanisms of regeneration in the human
body
 B. Induced
 Embryonic

stem cells:
Sources of ES:


 Adult
IVF
Nuclear Transfer
stem cells
 Stem



cells can be classified according to:
Potency
Source
Surface markers

Embryonic Stem Cells



From blastocysts left over from In-Vitro
Fertilization in the laboratory
From aborted fetuses
B. Adult Stem Cells

Stem cells have been found in the cord blood,
bone marrow, liver, kidney, cornea, dental
pulp, umbilical cord, brain, skin, muscle,
salivary gland . . .
 Embryonic
SC
 Pleuripotent
 Unlimited selfrenewal (Advantage
or disadvantage)
 Possibility of
rejection
 Adult
SC
 Multipotent
 Limited self-renewal
 Less
immunogenic?
 The
source of stem cells may be bone
marrow, peripheral blood, cord blood or
adipose tissue.
 Formerly, organ specific stem cells were used
(fetal or xenogenic)
 There
are two types of BM stem cells: HSC &
side population SC
 Advantages:
 1.More
efficient
stem cells (high
telomerase activity)
 2.Higher plasticity
 3.Cheap
 Disadvantages:
 1.
Low frequency
(1% CD34, 0.01%
MSCs)
 2. Painful
procedure of
acquisition
 3. Life span
decreases with age
 Adult
bone marrow-derived mesenchymal
stem cells (MSCs) are multipotent cells that
are the subject of intense investigation in
regenerative medicine . They are one of the
“side-population” stem cells found in the
bone marrow.
 MSCs
represent 0.001-0.01% of marrow
nucleated cells. However, they have several
advantages:
 1. Easy isolation
 2. High expansion potential
 3. Stable gene expression
 4. Reproducible chch
 Advantages:
 Disadvantages:
 1.Non-invasive
 1.
 2.
Large quantities
?function
 Advantages:
 Disadvantages:
 1.
 1.
Availability
 2. Non-invasive
 3. Cheap
HLA- mismatch
 2. Immature cells
 3. Low plasticity
 1.
Hematologic reconstitution: classical use
 2. Regenerative medicine
 3. Gene therapy
 4. Immunotherapy
 Stem
cells are now proven to effectively
regenerate various tissues. The following are
the clinical applications for stem cells in
regenerative medicine:
Transdifferentiation
Endogenous SC.
activation
Immunomodulation
Mechanisms
Of action
Angiogenesis
Growth factors
release
Over 4,500 clinical trials on stem cell therapy
in 140 countries , 2,230 are running and FDA
approved
In an average lifetime, human lungs take 2040 million breaths and experience a daily
airflow of between 7000 and 10,000 litrs.
 Mammalian lungs are made up of two distinct
regions:



1. The conducting airway tubes, including the
trachea, bronchi, and bronchioles.
2. The gas exchange regions, or alveolar
spaces.
 As
all body organs, lungs are rich in stem
cells and progenitor cells. In normal lungs,
progenitor cells are present in abundance
throughout each region. These cells divide to
replace old or damaged lung cells, which
keeps the lung healthy. The progenitor cells
include:
 tracheal basal cells,
 bronchiolar Clara cells, and
 alveolar type 2 cells.
 I.
Tissue Regeneration
 II. Vascularization
 III. Immunomodulation


The question of whether non-lung stem and/or
progenitor cells, whether embryonic or adult in
origin, can engraft and acquire phenotype of
structural lung cells following either systemic or
direct intratracheal administration remains
controversial.
Several promising and provocative reports appeared
in the early 2000's suggesting that bone marrowderived cells including hematopoietic stem cells,
MSCs, multipotent adult progenitor cells, and other
populations could structurally engraft as mature
differentiated airway and alveolar epithelial cells or
as pulmonary vascular or interstitial cells in mouse
models as well as following clinical bone marrow or
lung transplantation
 Later
studies also examined potential
engraftment using stem and progenitor cells
isolated from other tissues such as adipose,
placenta, cord, blood, and others.
 Systemic
administration of different
populations of bone marrow-derived cells
results in rare epithelial engraftment but
can stimulate pulmonary vascular growth.
 Through
in vitro studies, animal models, and
clinical trials in non-lung diseases, it has
been demonstrated that MSCs can suppress
activation, proliferation, and effector
functions of cells in both the innate and
adaptive immune system, as well as
promoting the development of immune cells
typically associated with immune suppression
such as T-regulatory cells
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Pulmonary fibrosis
Current hypotheses suggest that pathogenesis results from a
chronic indolent uncontrolled cycle of epithelial damage and
fibroblast activation.
In the first study to demonstrate ameliorating effects of MSCs in
lung injuries, mice were exposed to a lung fibrosis-inducing
agent, bleomycin, followed by systemic MSC
administration. Although only a small number of MSCs appeared
to have engrafted in the lung, significant reductions in lung
inflammation and damage, collagen deposition, and other
markers of injury occurred.
A subsequent study suggested interleukin-1α receptor antagonist
(IL-1αRA) secreted by the MSCs as responsible for the antiinflammatory effects.
A number of other reports have since confirmed the beneficial
effects of MSC administration in the bleomycin model of
pulmonary fibrosis although the mechanisms by which the MSCs
are acting have not yet been fully elucidated.
Acute lung injury/sepsis
 Acute lung injury (ALI) is a result of local or
systemic inflammation that leads to disruption of
the alveolar-capillary interface, leakage of
protein rich fluid and inflammatory cells into the
interstitium and alveolar space, and extensive
release of inflammatory cytokines.
 MSC administration generally improved survival
and function of sepsis-damaged organs such as
the kidney. In parallel, both lung inflammation
and levels of circulating proinflammatory
cytokines and chemokines were improved by MSC
treatment. MSC treatment also resulted in
significantly decreased bacterial burden and
enhanced bacterial phagocytosis and clearance.

 Several
mechanisms have been proposed to
explain these findings:




release of soluble mediators by MSCs that may
work in part to enhance antibacterial and antiinflammatory effects of inflammatory cells such
as macrophages and neutrophils.
MSCs themselves are capable of secreting at least
one antimicrobial peptide, the human
cathelicidin antimicrobial peptide hCAP-18/LL37.
MSCs may also be useful in preventing ischemiareperfusion injury.
These preclinical studies demonstrate that MSCs
may be useful in clinical sepsis and septic shock
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Pulmonary hypertension
Although EPCs have been more heavily investigated for use
in pulmonary hypertension, several reports have
demonstrated efficacy of MSC administration in both mice
and rats.
As with EPCs, it is not clear whether the MSCs themselves
participate in angiogenesis or whether secretion of antiinflammatory substances ameliorate the experimentally
induced injury that results in vascular obliteration.
Further, MSCs genetically engineered to overexpress
molecules known to have beneficial effects in pulmonary
hypertension such as endothelial nitric oxide synthase,
prostacyclin, or heme oxygenase 1 were even better able
to offer protective effects and in some cases, completely
reverse the pulmonary hypertensive phenotype and
increase survival.
MSCs may thus be a valuable alternate or adjunct to use
of EPCs for treatment of pulmonary hypertension.
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Bronchopulmonary dysplasia
In diseases of prematurity, pulmonary hypoplasia and
bronchopulmonary dysplasia account for 70% of
neonatal mortality.
Several recent studies demonstrate efficacy or MSC
administration in rodent models of hyperoxic lung
injury, utilized to understand mechanisms of
bronchopulmonary dysplasia pathogenesis.
PGE2 and tumor necrosis factor-inducible gene 6
(TSG-6) secreted by the MSCs have been suggested to
mediate the MSC effects in these models.
However, the overall mechanisms of MSC effects to
ameliorate hyperoxia-induced lung injury remain
unclear. However potential clinical use of MSCs in
infants remains a controversial subject.
Chronic obstructive airways diseases: asthma,
emphysema, bronchiolitis obliterans
 Allergic asthma, defined as airways
hyperresponsiveness and inflammation in
response to an inhaled allergen, is a disease
driven by dendritic cells, CD4 Th2 lymphocytes
and B lymphocytes.
 As proliferation and specific immune effector
functions of each of these cell types can be
inhibited by MSCs in vitro, allergic asthma is a
logical choice for potential intervention with
MSCs. As such, there are now a number of
studies demonstrating amelioration of airways
hyperresponsiveness and lung inflammation in
mouse models of allergic airways inflammation.
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Notably, MSCs can inhibit both the initial allergen
sensitization as well as the subsequent response to an
allergen challenge in a previously sensitized animal.
Some specific mechanisms of MSC actions have been
defined in these models including shifting of antigenspecific CD4 T cell phenotype from Th2 to Th1 as well
as upregulation of T-regulatory T cells by release of
transforming growth factor β (TGFβ) by the MSCs.
Each of these actions can ameliorate allergic airways
inflammation. Likely there are other mechanisms of
MSC actions involved that are still to be elucidated.
Given the positive results in these studies, it is likely
that clinical trials of MSCs in severe asthma will occur
in the near future.
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Lung cancers
Bone marrow-derived MSCs and EPCs may contribute to
development of primary and metastatic lung carcinoma
and other malignancies, notably breast and ovarian
cancers, in mouse models. These cells function, in part, by
providing a supportive stroma for the cancers and/or by
participating in tumor vascularization.
In contrast, MSCs and EPCs have been demonstrated to
home to areas of tumor development and EPCs and MSCs
engineered to secrete antitumor agents have been utilized
to suppress tumor growth in mouse tumor models of
primary lung cancers, metastatic lung cancers, and of
other cancers metastatic to the lung.
Cell-based therapies may thus be useful in lung cancer
therapeutics.
 This
study was done to investigate the effect
of CB-MSCs on amiodarone lung fibrosis
murine model
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‫المجاالت الهامة فى الدول اإلسالمية‬
‫‪ ‬تشجيع التعاون العلمى فى أبحاث الخاليا الجذعية‬
‫بين الدول األعضاء‬
‫‪ ‬تخضع التجارب اإلكلينيكية للضوابط الطبية األخالقية‬
‫و تعليمات لجان أخالقيات البحث العلمى‬
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